Anti-CRISPRs Oligonucleotides Facilitate Cell Type-Specific Control of Nanoparticle Cas9 Gene Editing
Fitzgerald, Jordan Paul
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While CRISPR-Cas systems represent a powerful research tool, in order to become clinically viable significant challenges woud have to be overcome. One of the largest issues facing the breadth of CRISPR technologies is the lack of cell type specific gene editing outside of hepatocytes. Controlling the cell type-specific activity of CRISPR-based drugs would enable new Cas9 therapies. Natural anti-CRISPRs can inhibit gene editing, suggesting that synthetic anti-CRISPRs delivered to ‘off target’ cells could limit undesired gene editing in vivo. This report shows that anti-CRISPRs termed inhibitory oligonucleotides (iOligos), which target single guide RNA (sgRNA) via a Rnase H15 independent mechanism, can modulate gene editing in adult mice. By delivering iOligos to hepatocytes, Cas9 hepatocyte editing is blocked, altering the tropism of a nanoparticle so it preferentially edits genes in the spleen. This represents a technology by which it is possible to markedly suppress gene editing in hepatocytes without reducing splenic editing. Synthetic anti-CRISPRs can improve the reach and specificity of Cas9 therapies in adult mammals without improvements in drug delivery vehicles like new nanoparticles.